GLYCOGEN STORAGE DISEASE

TYPE 1
HNSC 7231: Pediatric Nutrition
Professor Miller-Zentman MS RDN CNSC

Adina Lapine
[email protected]
 Introduction

Glycogen Storage disease was first described in 1929 by Alfred Von Gierke after observing excessive

glycogen in the liver and kidneys of two children1. Since then, GSD has evolved into a group of 16 forms

involving different enzymes in glycogen metabolism in different organs (mainly the liver or the muscle)

and with varying severities. In commemoration of his work, GSD type 1 is alternatively named Von

Gierke’s disease. It is known to affect 1/100,000 live births in the general population, and 1/20,000 births

in the Ashkenazi Jewish population1. Although Von Gierke’s disease is classified as a hepatic GSD, it has

a body wide impact and is actually considered the most severe form of GSD2. Common complications

include renal and liver problems, osteoporosis, gout, pancreatitis, as well as decreased immunity and IBD

in type 1b. As dietary treatment has extended the life span of the GSD patient, nutritional management

has moved from promoting euglycemia to preventing the chronic dysfunctions found in GSD type 1 that

decrease quality of life.

Pathophysiology

Glycogen is the storage form of glucose in the human body. It is highly branched which makes it more

soluble and decrease the time it takes to mobilize glucose to the blood. In GSD type 1, glucose removed

from glycogen is not able to be released from the liver and kidneys. GSD type 1 has been further divided

into subtypes 1a and 1b because it involves mutations of two different genes that results in slight

variations in manifestation. In GSD 1a, there is a mutation on the G6PC gene that codes for glucose-6-

phosphatase3. G6Pase is an enzyme located in the endoplasmic reticulum. It is required to convert glucose

6 phosphate to glucose, which is the last step of glycogenolysis and gluconeogenesis before the glucose

can be sent out to the blood. In GSD 1b, there is a mutation on the SLC37A4 gene that codes for the

glucose-6-phosphate transporter that brings glucose-6-phosphate into the endoplasmic reticulum so it can

be acted upon by G6Pase3. Both of these enzymes result in the lack of glucose being sent out to the blood,

and instead building up in the liver and the kidneys1.

the body tries to obtain energy in other ways. After a meal, when glucagon is high, the liver is stimulated

to release glucose. Since glucose is stuck in the liver as glucose-6-phosphate, it goes to the glycolytic

pathway where it is broken down to pyruvate and lactate, leading to lacticacidemia3. GSD 1 can result in

hyperlipidemia and hypertriglyceridemia: The excess pyruvate and acetyl coA from glycolysis of G6P

may be used to form fats and triglycerides. Additionally as glucagon levels persist, fat cells start to release

fatty acids3. Hyperuricemia results from the build up of uric acid due to increased production and/or

decreased excretion as it competes with lactic acid for excretion in the renal tubules3. In GSD type 1a, the

excess glucose will go to the pentose-6-phosphate pathway and produce uric acid as a byproduct3.

GSD type 1 is not confined to problems in obtaining energy. The liver develops hepatomegaly due to the

build up of glycogen and fat. Liver abnormalities such as adenomas and cancer are common in

adulthood1. The kidneys develop nephromegaly due to a build up of glycogen, which combined with the

metabolic disturbances above lead to tubular and glomerular dysfunctions that cause problems in

electrolyte balance in the urine. Calcium, phosphate and vitamin D are lost in large amounts while

inadequate citrate is released, leading to nephrolithiasis and nephrocalcinosis1. This can eventually cause

end stage renal disease requiring kidney transplantation1. Patients can develop pancreatitis and xanthomas

due to hypertriglyceridemia and hypercholesterolemia3.

GSD type 1b also has all the problems mentioned above as well as neutropenia and decreased neutrophil

function and amount. This is believed to be caused by an inadequate amount of NADPH being produced

in the pentose phosphate pathway (due to the lack of the enzyme that brings glucose-6p into the

endoplasmic reticulum)3.

Nutritional Management

The main nutritional problem in GSD 1 is maintaining euglycemia (>70 mg/dl glucose). This is

accomplished by earing carbohydrates throughout the day and monitoring blood glucose. Infants must be
fed every 2-3 hours with breastmilk or a formula that is lactose, fructose and sucrose free4. When babies

begin to sleep overnight, they must either be woken up to eat, have overnight glucose infusions, or be fed

enterally1. The GIR for infants is the highest at 8-10 mg/kg/min)4. Infants should eat as soon as they wake

up to prevent hypoglycemia, as insulin levels are still high from the overnight feed4. Once babies are

around six months and have adequate pancreatic amylase, the parents can introduce corn starch feeds4.

Uncooked corn starch is a mainstay of glycemic control in GSD due to its slow digestion and subsequent

slow glucose entry into the blood preventing the need to release glycogen. Young children should be

given 1.6 g/kg of cornstarch every 3-4 hours. The corn starch can be mixed into formula, or for older

children, water and diet drinks. Care should be taken that it is not mixed into hot drinks or acidic drinks

like lemonade which can reduce its effectiveness4. The corn starch is mixed with fluid at a ratio of 1 g/2-3

ml4. Parents should not overfeed corn starch as it can cause excess weight gain, excess glycogen storage,

and insulin resistance4. Children should consume carbohydrates every 4-6 hours. The calorie requirement

is calculated according to weight, height, and physical activity. A third of the calories is provided during

the overnight feed. The recommended macronutrient distribution is 60-70% carbohydrates, 10-15%

protein and less than 30% fat4. The carbohydrates should be complex so that glucose enters the blood

slowly. Since galactose and fructose are known to increase lactic acidemia and hyperuricemia, children

are limited to 2.5 g fructose per meal and 1 serving of dairy per day4.

Blood glucose should be checked upon awakening, before eating and before exercise4. Blood glucose has

traditionally been monitored with finger sticks, however, as CBGM (continuous blood glucose

monitoring) becomes more popular, they are being tested in the GSD population4. One study of 16

children with GSD 1 in Turkey aimed to examine the safety and efficacy of CBGM in pediatric GSD type

1 patients5. In the first phase, the subcutaneous devices were worn for 72 hours. During this time,

nurses/parents measured blood glucose by finger stick. Doctors provided parents with dietary

recommendations based on the blood glucose readings. The patients underwent CBGM 3-6 months later

to see if their blood glucose control had improved. Liver enzymes and metabolic indicators were
measured at the start and end of the trial. The researchers found that CBGM and traditional blood glucose

readings were similar. Upon completing the trial, patients showed decreased liver size, liver enzymes,

serum triglycerides, serum lactic acid and hypoglycemic episodes. The researchers concluded that CBGM

can prevent asymptomatic hypoglycemia and improve metabolic indicators5.

Other nutritional problems in GSD type 1 include poor growth, osteoporosis, kidney problems, anemia,

pancreatitis, and gout. Poor growth is related to poor metabolic control and lack of nutrients. The child

may be lacking nutrients important for growth due to displacement by corn starch and a restricted diet.

This is avoided by giving corn starch only after a meal and providing a multivitamin4. Osteoporosis may

be averted by glucose control but needs to be frequently assessed with DEXA1. Calcium and vitamin D

need to be given in the form of milk substitute or multivitamin1. It is important to prevent kidney damage:

Kidney stones can be prevented by metabolic control and taking a citrate supplement. Calcium deposition

can be avoided by adequate hydration, a no salt diet, and magnesium supplement. If microalbuminuria is

observed, the patient will need pharmacotherapy like ACE inhibitors or ARB’s1. Kidney damage can be a

cause of anemia due to the lack of erythropoietin1. Other causes of anemia include a restricted diet (iron,

folate, B12), iron deficiency from increased production of hepcidin), and bleeding (poor platelet function,

IBD)1. Anemia may be treated with EPO infusion, iron infusions and multivitamin1. Pancreatitis is related

to hypertriglyceridemia which is controlled with glucose control. In one case study, a 22 month female

who was later determined to have GSD type 1 presented with acute pancreatitis and elevated TG (3791

mg/dl) after being fed large amounts of pastries6. After being discharged with a sugar restricted diet

(except glucose), her TG levels improved6. Gout can be prevented by metabolic control, the drug

allopurinol, and a low purine diet. In one case study, a 25 year old man with GSD presented to the

hospital with tophi wounds on his right ring finger7. He was found to have hyperuricemia (800

micromol/L), hypertriglyceridemia and hypercholesterolemia. He had hepatomegaly and calcium

deposition in the kidney. After the wound was treated, he was put on corn starch feeds four times a day,

given allopurinol and placed on a low purine diet. After seven months, no new tophi had formed7.
Drug interactions can include drugs that cause hypoglycemia like antidepressants and beta blockers1.

Growth hormone can cause hypertriglyceridemia1. NSAIDs can be nephrotoxic and exacerbate bleeding1.

Citrate supplements should not be taken at the same time as corn starch feeds1.

Research Questions

More research is required on the best way to manage nutrition in the GSD 1 population. One area that is

shockingly lacking is the restriction of foods containing galactose and fructose. After a 1956 study found

that these two sugars increase lactic acidosis, doctors restricted intake of dairy, fruits and vegetables2.

This has led to significant nutrient deficiencies related to most of the complications of GSD today.

Researchers are also interested in the best form of carbohydrate for overnight feedings. Small scale trials

have been launched into waxy maize starch, which has an extended period of glycemic release, and other

starches such as manioc, but patients are often left to choose according to preference and tolerance2. A

significant gap in the current knowledge is why patients who have adequate glycemic and metabolic

control still experience abnormalities, especially hypocitraturia that leads to kidney problems. Some

speculate that GSD patients develop tubular acidosis independent over time1.

Questions to ask in an assessment

Question 1: Does the patient keep a blood glucose log? Does it show poor blood glucose control?

Rationale: It is important for the parents to monitor blood glucose upon awakening and before meals to

ensure that the child has good control. If they do not keep a log, I will advise them to do so in the future

as it is possible for a child to experience asymptomatic hypoglycemia. If the child is showing

hyperglycemia after awakening or before meals, it could mean that the corn starch foods need to be

decreased. If there is hypoglycemia, the corn starch feeds might need to be increased, or given closer

together. If corn starch feeds do not help, the child may need intravenous glucose infusion.

Question 2: Does the child experience gastric distress?

not well tolerated, there are other slow releasing carbohydrates that have been tested in small scale trials,

including sweet manioc starch and waxy maize heat modified starch. Alternatively, the child may be

suffering from IBD, in which case they may need treatment with traditional IBD medications or a

probiotic.

Question 3: Is the patient growing normally?

Rationale: Growth is an indicator of metabolic control. If she has poor growth, I would want to see a

blood glucose log and provide parents with strategies to control glucose. If glucose control is ok, I would

ensure that the patient is receiving adequate protein and nutrients important for growth and bone

mineralization.

Question 4: Does the patient present with symptoms of anemia (lethargic, pale, cognitive delays)?

Rationale: Anemia is a common complication in GSD 1 children. It can be related to a poor diet, in which

case iron supplementation and multivitamin would be warranted, or to more severe causes such as hepatic

adenoma and bleeding. I would ask the parents if they notice dark stools or if the child bleeds a lot. If yes,

she would need to be assessed for IBD or given medications that assist with blood clotting. EPO

administration will be required if she had kidney damage.

Conclusion

GSD type 1 is caused by one of two genetic defects in carbohydrate metabolism and is managed by

manipulation of the diet. Children with GSD type 1 must strictly control their blood glucose or risk

developing metabolic abnormalities that can cause damage to most organs. The main dietary intervention

is to make up for the lack of glycogen by ingesting uncooked corn starch that promotes the long term

release of glucose. The other strategy, to restrict fruits, vegetables and dairy, causes nutrient deficiencies

that contribute to the debilitating nature of GSD. Although the life expectancy of patients with GSD has
improved, their quality of life has not as they are prone to develop kidney failure, osteoporosis, and gout.

Further research is needed as to why these problems persist despite seemingly adequate metabolic control.
 References

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